With increasing risk of nuclear detonation there is a need for effective medicinal counter-measures that can be delivered after exposure to prevent radiation-induced mortality. Adding to this need, mortality increases significantly when radiation is combined with injury (RCI). Thousands of people injured by nuclear detonation are expected to die from what was considered a sub-lethal radiation exposure. Therefore, agents to mitigate effects of radiation and RCI must be developed and stockpiled for emergency use. TP508 (rousalatide acetate), a novel peptide drug that is currently in clinical trials with established safety and manufacturing, stimulates angiogenesis and tissue repair by attenuating inflammation, preventing apoptosis, stimulating nitric oxide (NO) production, and reversing endothelial dysfunction. Preliminary studies suggest that TP508 attenuates radiation-induced apoptosis, reverses radiation-induced endothelial dysfunction, and stimulates healing in irradiated rats. Because apoptosis, endothelial dysfunction, and delayed healing are associated with early radiation damage and subsequent effects leading to mortality, these results predict that TP508 treatment will counteract lethal effects of radiation and RCI in multiple tissues and at multiple points in the disease process. In this project, we will use gamma irradiated C57BL/6 mice to test the potential efficacy of TP508 as a countermeasure for radiation exposure and RCI. Specific aims for this Phase 1 project will be: 1) to determine whether TP508 application to wounds or injection into mice reduces mortality due to radiation or RCI, and if this treatment accelerates wound healing in these mice;and 2) to determine whether TP508 affects systemic manifestations of radiation and RCI that include increased cytokine production, cellular apoptosis, and endothelial dysfunction. These Phase 1 studies will determine whether TP508 has potential to become a medicinal countermeasure for radiation and RCI-induced mortality. If TP508 reduces radiation or RCI mortality, Phase 2 studies will be proposed to complete FDA requirements to initiate clinical trials with a goal of government licensing and National Stockpiling of this drug for emergency use. PUBLIC HEALTH RELEVANCE: Following a nuclear detonation the combination of radiation and traumatic injury is expected to be much more deadly that radiation alone. TP508, a novel peptide drug with established manufacturing and safety, works through mechanisms thought to counteract effects of radiation. In this project, we will determine whether TP508 can prevent lethal effects of radiation and injury in irradiated animals as a first major step in development and potential FDA approval of TP508 as a drug to reduce the risk of death from radiation exposure.